Targeting Kdm6a in Microglia Reverses MS-Like Disease in Female Mice

A new study suggests that a gene located on the X chromosome—Kdm6a—may play a key role in the increased susceptibility of women to multiple sclerosis (MS). Researchers found that deleting this gene specifically in microglia, the brain’s resident immune cells, significantly reduced disease severity in female mice with an MS-like condition, while having minimal effects in males.

MS affects women roughly three times more often than men, but the biological mechanisms driving this disparity remain incompletely understood. Kdm6a, which encodes a histone demethylase, is one of the few genes on the X chromosome that escapes inactivation, meaning it is expressed at higher levels in females than in males. The research team hypothesized that this gene could influence microglial behavior in a sex-specific way, contributing to disease pathology.

To test this, they used a mouse model of MS known as experimental autoimmune encephalomyelitis (EAE) and selectively deleted Kdm6a from microglia. In female mice, this genetic deletion led to a notable reduction in neuroinflammation. Pathological signs of disease were alleviated, markers associated with disease-activated microglia were reduced, and markers of resting, homeostatic microglia increased. Additionally, the deletion reversed widespread changes in the translatome—the set of actively translated genes—in the spinal cord.

In contrast, male mice with the same microglial Kdm6a deletion showed only minor improvements in EAE, underscoring the sex-specific role of the gene.

The study also tested metformin, a diabetes medication known to inhibit the enzymatic activity of KDM6A. In female mice, metformin treatment mimicked the effects of genetic deletion: it ameliorated disease symptoms and normalized the microglial translatome. However, the drug had little impact on EAE in males, further reinforcing the idea that KDM6A activity is more functionally relevant in female microglia during neuroinflammation.

To investigate how KDM6A might exert its effects at the molecular level, the researchers performed CUT&RUN and sequencing analysis to identify genes directly bound by the protein in microglial nuclei. When these binding data were compared with gene expression profiles from the same tissues, a clear correspondence emerged—indicating that KDM6A binding influences microglial gene activity during disease.

Finally, the team turned to human data. Transcriptomic analysis of human microglia confirmed that KDM6A is more highly expressed in women than in men. Moreover, in MS patients, gene dysregulation in microglia was more extensive in women than in men, further implicating KDM6A in the sex bias of MS pathogenesis.

Altogether, the findings highlight KDM6A as a key epigenetic regulator in female-biased neuroinflammation. By linking sex-linked gene dosage to disease-driving microglial behavior, the study opens the door to sex-specific therapeutic strategies—potentially involving KDM6A inhibition—for autoimmune neurodegenerative disorders like MS.